ArticleThe Journal of biological chemistry2021
Heterodimer formation with retinoic acid receptor RXRα modulates coactivator recruitment by peroxisome proliferator-activated receptor PPARγ.
Article in The Journal of biological chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- Molecular Pathways Linking High-Fat Diet and PMBiomolecules · 2024Pooled it
- Selenoprotein H Functions as a PPARα Coactivator to Link Selenium Homeostasis to Hepatic Lipid Metabolism and Protect against Steatohepatitis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- DNA induces non-canonical dimerization of the farnesoid X receptor.Nucleic acids research · 2026Article
- Nuclear receptors in health and disease: signaling pathways, biological functions and pharmaceutical interventions.Signal transduction and targeted therapy · 2025Review
- PPARG-centric transcriptional re-wiring during differentiation of human trophoblast stem cells into extravillous trophoblasts.Nucleic acids research · 2025Article
- A generalizable approach for programming protease-responsive conformationally inhibited artificial transcriptional factors.Nature communications · 2025Article
- Early-life vitamin A supplementation modulates the skeletal muscle transcriptome and intramuscular fat deposition in feedlot-finished beef steers.Journal of animal science · 2025Article
- The role of PPARγ in cancer cachexia: friend or foe?Frontiers in endocrinology · 2025Review
- PPARγ alleviates preeclampsia development by regulating lipid metabolism and ferroptosis.Communications biology · 2024Article
- Inflammaging and fatty acid oxidation in monocytes and macrophages.Immunometabolism (Cobham, Surrey) · 2024Review
- Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation.Journal of the American Chemical Society · 2023Article
- Article
- Druggability Evaluation of the Neuron Derived Orphan Receptor (NOR-1) Reveals Inverse NOR-1 Agonists.ChemMedChem · 2022Article
- Cooperativity as quantification and optimization paradigm for nuclear receptor modulators.Chemical science · 2022Article
- Therapeutic Effects of Retinoic Acid in Lipopolysaccharide-Induced Cardiac Dysfunction: Network Pharmacology and Experimental Validation.Journal of inflammation research · 2022Article
- The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Xanthines.ACS pharmacology & translational science · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nuclear receptors (NRs) activate transcription of target genes in response to binding of ligands to their ligand-binding domains (LBDs). Typically, in vitro assays use either gene expression or the recruitment of coactivators to the isolated LBD of the NR of interest to measure NR activation. However, this approach ignores that NRs function as homo- as well as heterodimers and that the LBD harbors the main dimerization interface. Cofactor recruitment is thereby interconnected with oligomerization status as well as ligand occupation of the partnering LBD through allosteric cross talk. Here we present a modular set of homogeneous time-resolved FRET-based assays through which we investigated the activation of PPARγ in response to ligands and the formation of heterodimers with its obligatory partner RXRα. We introduced mutations into the RXRα LBD that prevent coactivator binding but do not interfere with LBD dimerization or ligand binding. This enabled us to specifically detect PPARγ coactivator recruitment to PPARγ:RXRα heterodimers. We found that the RXRα agonist SR11237 destabilized the RXRα homodimer but promoted formation of the PPARγ:RXRα heterodimer, while being inactive on PPARγ itself. Of interest, incorporation of PPARγ into the heterodimer resulted in a substantial gain in affinity for coactivator CBP-1, even in the absence of ligands. Consequently, SR11237 indirectly promoted coactivator binding to PPARγ by shifting the oligomerization preference of RXRα toward PPARγ:RXRα heterodimer formation. These results emphasize that investigation of ligand-dependent NR activation should take NR dimerization into account. We envision these assays as the necessary assay tool kit for investigating NRs that partner with RXRα.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.